Plant and human immune systems are closer than we think, study finds

Few living things seem to have less in common than plants and animals, but that assumption is being increasingly challenged. Evolution, and the ways in which the kingdom of plants and the kingdom of animals that munch on them have grown up together, leave their traces even after hundreds and hundreds of millions of years. A study published last month in Nature Plants describes shared biochemical pathways involved in vitamin B6 levels that link human neurological health and plant immunity in ways that may teach us how plant immunity works — and how to better treat neurological conditions, like epilepsy, in humans.

“We’ve always been intrigued by overlap between plants and humans,” study coauthor Pradeep Kachroo, a botany professor at the University of Kentucky, told Salon in a video interview.

The last common ancestor of plants and animals was a little single-celled organism that lived around 1.5 billion of years ago. One descendant of our last common ancestor went on to engulf a photosynthetic bacterium, which would then toil away harnessing the power of the sun to fuel this progenitor of all plants. (The common ancestor had earlier engulfed a different bacterium that became the mitochondrion, an organelle that fuels both plant and animal cells). A different descendant of that common ancestor went on to give rise to all animals and fungi. It’s like a fairy tale: one brother goes off to found the kingdom of plants, and the other strikes his own bold path to become the first member of the kingdom of animals and fungi.

Today, the descendants of those evolutionary royals of old are very different indeed. Typically green, plants generally stay rooted, soaking up solar energy and converting it to chemical energy. The animals, meanwhile, depend on our evolutionary siblings: we either eat vegetation or something else that does, and thus generate our own energy by consuming theirs. Other than the dependence that results in one eating the other, we would seem to have basically nothing in common.

Plants use an amino acid called lysine for many things, including as a part of their detection and response to pests. Kachroo’s lab was trying to understand what pipecolic acid does and how it functions, and also what role N-hydroxypipecolic acid plays in immunity. As part of this work, Huazhan Liu, Kachroo’s postdoctoral scholar and this study’s lead researcher, was trying to clarify how the amino acid lysine gets broken down and used in plants. Her subject was Arabidopsis thaliana, a mustard also known as mouse-ear cress, that has been described as a model plant for genome gnalysis.

One metabolite, or product, of lysine produced during this process is called pipecolic acid, and another, produced at a later step, is called N-hydroxypipecholic acid. Liu observed that these two amino acids were appearing at different concentrations. 

Kachroo, speaking from Kentucky, recounted the story to Salon in a video interview while Liu joined the call from China.

“Pipecolic acid was much more abundant than hydroxycholic acid,” Kachroo explained. If one thing (the substrate, in the language of chemical reactions) is being converted to another thing — the product, the amount of the substrate should almost equal to the product. Something couldn't be right.

“I have this much here. I have very little here.” Liu began to wonder if perhaps something else was using pipecolic acid as a substrate, using it up so that there was less left over for the expected production of N-hydroxypipecolic acid.

Now, lysine is found in all sorts of organisms, and the way it's catabolized is pretty well-understood in animals. In plants, some of the steps are less well understood. 

So in a striking act of scientific creativity, Liu turned to the animal kingdom and to human medical science to figure out what was going on.

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She realized that, while it’s not an essential amino acid for us, pipecolic acid is also present in humans.

As Liu learned, if you, a human, eat your distant vegetable brethren, you can get a lot of pipecolic acid in your diet: cucumbers, for example, are high in it. You can also consume lysine itself, as it's also found in plants or sold as supplements. Our gut bacteria breaks down that dietary lysine into pipecolic acid, and lysine may also be converted to pipecolic acid by an enzyme already present in the human body. 

Liu then wondered whether perhaps a similar enzyme exists in plants. She found it, characterized it biochemically, genetically and enzymatically, created plants that made too much of it… and then realized that this enzyme was not, in fact, unknown to science. But in plants, it was called sarcosine oxidase, because it was (incorrectly, as we now know) believed to break down a different chemical, sarcosine.

“We realized it has nothing to do with sarcosine, but it has everything to do with pipecolic acid,” Kachroo told Salon. This is what was using up the missing pipecolic acid, resulting in less N-hydroxypipecolic acid where more was expected.

In the plant, then, lysine gets converted to pipecolic acid, and then this enzyme converts it to P6C, or Δ1-piperideine-6-carboxylic acid, yet another step in the lysine catabolism pathway. But P6C is familiar to medical doctors who work with humans, not plants. That’s because there is a type of epilepsy that results when a mutation causes the body to increase P6C production until it accumulates in the body. The excessively high neurotransmission that results produces the symptoms we know as epilepsy. 

This kind of epilepsy is called pyridoxine-dependent epilepsy, because it’s treated by giving the patient heavy amounts of vitamin B6, or pyridoxine. The doctors use a form of B6 because it reacts chemically with P6C, taking up the excess P6C. In plants, overly high P6C levels likewise mess with vitamin B6 levels, disrupting the delicate balance of different types of B6 and causing neuropathology in the plants, just as it does in humans.

This study sheds light on evolution in two ways: we can see how biochemical pathways common to two entirely separate kingdoms of life, plants and animals, have been largely conserved through our long history apart. And we can see how we have evolved in tandem. Enzymes found in plants (and probably originally acquired by them through horizontal transfer of genes from bacteria: evolution is super messy) and animals have been repurposed to regulate the levels of vitamin B6 — which we humans can’t make ourselves but, supplements aside, only get from plants — in very similar ways.

“Why is it that humans ‘decided,’ over the course of evolution, to build a pathway which is based on a plant diet, to regulate their vitamins which they are, again, getting from a plant diet? Humans do not make vitamins; vitamin B6 we derive from a plant diet. So they are regulating two components which self-regulate each other. Why? It’s because you need a balance. Because if you have too [little] of vitamin B6 you cause problems. If you have too much of vitamin B6 you cause problems,” Kachroo told Salon.

And yet, vitamin B6 supplements are sold without prescription and without warning at every pharmacy or health food store or grocery, with no regard to the delicate balance by which we naturally regulate the amounts of this vitamin we get from our diets.

“When we are taking these medicines, we’re not realizing how much we are consuming,” Kachroo said, mentioning a woman in treatment for epilepsy who approached him in Mexico after he spoke at a conference there. She told him she was taking B vitamins. Indeed, the amount she was taking far exceeded daily requirements — and the Mexican diet already contains ample B6: avocado is one of the richest sources of it.

Like plants, which can develop neuropathological problems, becoming susceptible to invasion by pathogens, if their vitamin B levels are too high or too low, a patient like the one with whom Kachroo spoke could be at risk of epileptic symptoms simply because she’s supplementing a natural diet with additional B6. It can be risky messing with nature.

“We become,” Kachroo told Salon, “who we are based on the diet we consume.”